The objective of this research is to define the mechanisms mediating pregnancy induced hypertension. The central hypothesis to be tested in this proposal is that a reduction in uteroplacental perfusion pressure causes hypertension by reducing renal-pressure natriuresis. The reduction in pressure natriuresis occurs as a result of placental and/or leukocyte-derived cytokines causing endothelial cell activation that leads to enhanced formation of endothelin. These abnormalities reduced renal plasma flow and glomerular filtration thereby decreasing renal sodium excretory function. To test this hypothesis, arterial pressure, renal, hormonal, and endothelial function will be examined in a conscious, chronically-instrumented rat model of chronic PIH produced by long-term reductions in uterine perfusion pressure (RUPP). In addition, in vitro studies utilizing endothelial cell culture will be used to determine the interaction between inflammatory cytokines, sex steroids and endothelin production. Specific aims to be addressed are: 1) To test the hypothesis that abnormalities in cardiovascular and renal function during chronic reductions in uteroplacental perfusion pressure are due to elevations in maternal plasma levels of inflammatory cytokines such as TNF alpha and IL-6; 2) To test the hypothesis that estrogens and/or progesterone enhance the endothelial activation and hypertensive response to TNF alpha and IL-6 .